On December 7, 2023 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported updated preclinical data from its potent, selective and brain penetrant ErbB2 inhibitor program along with initial preclinical data from its newly disclosed H1047R mutant-selective PI3Kα inhibitor discovery program at the 2023 San Antonio Breast Cancer Symposium (SABCS), taking place December 5-9, 2023 at the Henry B. González Convention Center in San Antonio, Texas (Press release, Cogent Biosciences, DEC 7, 2023, View Source [SID1234638235]). The posters can be found in the ‘Posters and Publications’ portion of the Cogent website.
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"Broadening our pipeline of potential best-in-class targeted therapies remains key to our long-term strategy, and we are excited to provide an update on our selective, EGFR-sparing ErbB2 inhibitor, which features exceptional potency, half-life and oral bioavailability with potentially best-in-class brain penetrance to enable inhibition of mutations in CNS tissue," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "In addition, we are pleased to present initial data on our effort to design a potent H1047R mutant-selective PI3Kα inhibitor. This program aligns with our mission of creating best-in-class targeted therapies for patients with genetically defined diseases and is complementary to our efforts focused on the development of bezuclastinib in advanced and nonadvanced systemic mastocytosis and GIST."
ErbB2 Inhibitor
Presentation ID: PO3-26-02
Title: Identification of a novel, brain penetrant, EGFR sparing, ErbB2 inhibitor with activity against oncogenic ErbB2 mutations
Session: Poster Session 3
Date: Thursday, December 7, 2023
Time: 12:00 PM – 2:00 PM CT (1:00 PM – 3:00 PM ET)
Cogent is developing a potential best-in-class EGFR-sparing, brain-penetrant ErbB2 inhibitor that includes coverage of key mutations (YVMA, S310F, V842I, L755S) inadequately addressed by currently approved therapies. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification.
The poster presented today shows that CGT4255 demonstrated low nM potency against ErbB2 wild-type and oncogenic ErbB2 mutations with 100-fold selectivity over wild-type-EGFR. In addition to impressive selectivity across a broad range of kinases, receptors and ion channels, CGT4255 has exceptional half-life in human whole blood and liver cytosol fractions. Dose ascending PK data in mice showed low clearance and high oral bioavailability at all doses, with best-in-class 80% brain penetrance at 100 mg/kg. Maximum inhibition of pErbB2 was observed at a 30 mg/kg PO dose in both NIH/3T3 ErbB2-YVMA and ErbB2-L755S tumor models, with complete regressions at 100 mg/kg PO BID in the NIH3T3 ErbB2-L755S TGI model and was well tolerated. These advances continue to highlight a favorable profile for optimal clinical efficacy.
PI3Kα Inhibitor
Presentation ID: PO3-26-01
Title: Preclinical in vitro and in vivo characterization of a novel, wild-type-sparing, PI3Kα H1047R mutant-selective inhibitor
Session: Poster Session 3
Date: Thursday, December 7, 2023
Time: 12:00 PM – 2:00 PM CT (1:00 PM – 3:00 PM ET)
Cogent is developing a potential best-in-class, wild-type-sparing, PI3Kα inhibitor that provides coverage for the H1047R mutation, which affects >30,000 cancer patients each year. The phosphoinositide 3-kinase (PI3K) pathway is a key cell cycle regulating pathway that has an established role in tumor growth and development. PI3Kα mutations are highly prevalent in many solid tumors and are present in 36% of all breast cancer patients. The approved agents for these patients often lead to dose limitations, resulting from activity against wild-type PI3Kα.
The poster presented today highlights that CGT4824 is an allosteric inhibitor of PI3K, was well tolerated in the tumor growth inhibition efficacy models and has been profiled as lead series exemplar based on its selectivity for H1047R over WT PI3K. CGT4824 demonstrated low nM potency in H1047R mutant PI3K cell lines, differentiated dose ascending PK in mice with high bioavailability and low clearance. CGT4824 also showed >95% inhibition of pAKT in a H1047R PD model, importantly without increases in insulin or C-peptide. Its efficacy profile was superior to a clinically-relevant dose of alpelisib in the NCI H1048 mouse tumor growth inhibition model. Additional lead series analogs were also described, highlighting our more recent advances toward increasing selectivity and potency against H1047R mutants.